Companies in the pharmaceutical and biotechnology industries annually funnel huge monetary investments into research and development (R&D) of new medical technology, i.e., drugs, medical devices, and new methods or techniques to diagnose and treat medical disorders. The life cycle of any new medical technology generally originates in a laboratory, after which the new medical technology undergoes several phases of investigation to prove its safety and efficacy. Once a sufficient body of evidence has been amassed to assure such safety and efficacy, the new medical technology is sent before a regulatory committee for review. If the medical technology is subsequently approved, it can then be marketed for sale and sold, enabling the companies investing in that new medical technology to begin to realize the return on their investment in the development of the new technology. The life cycle for most of the new medical technology is lengthy; for example, as of 1997 the process of developing a new medical technology from laboratory to marketing took an average of 10 to 12 years.
Over the past decade a new industry has arisen as an adjunct to the clinical research process of developing new medical technologies. R&D service providing organizations, known as Contract Research Organizations (CROs) arose out of a growing need among the pharmaceutical and biotechnology companies to curb costs. Rather than hiring full-time research staff, companies turned to CROs as a resource for these companies to outsource the administrative and coordinating responsibilities for clinical research. Over time CROs compounded other value-added services to encompass a spectrum of services, including clinical trial coordination, monitoring of data collection, identification of quality research trial investigators and sites, and centralized laboratory testing. The development of the CROs was also logical for other reasons, including the favorable implications for the pharmaceutical and biotechnology companies to have their new medical technology tested under the unbiased eye of a third-party organization.
One of the greatest claims made by the CROs is the ability of their trained staff professionals to shorten the amount of time required to complete a research project, which would in turn shorten the amount of time required to pass regulatory scrutiny. As can be recognized from the protracted 10 to 12 year development period described above, such shortening of the life cycle time is very desirable for most pharmaceutical and biotechnology companies. This is especially true because while a newly invented drug or medical device may be patented upon discovery, with the 20 year patent term commencing on the date of filing of the patent application, such new medical technology does not become profitable until it is approved, marketed, and sold. Thus, if as described above, it can take 10 to 12 years for the new technology to become profitable, there will only be a limited portion of the patent term remaining.
It is not inconceivable that after spending millions on R&D and after facing a tough regulatory approval process, a pharmaceutical or biotechnology company would have but 2 to 5 years of exclusivity to exploit the exclusion sale of the new medical technology. Such outcome is ultimately detrimental: it discourages R&D in the medical field, encourages hasty clinical research to expedite the regulatory process, and places smaller to mid-sized companies at a distinct disadvantage to the established “health care giants.” The protracted pre-marketing time, particularly in the United States, has also been criticized as being a barrier to the passage of vital new medical technologies. In many cases, life-saving drugs can only be obtained in settings of research or in markets outside the control of the United States government.
Despite the emergence of the CROs, their services are still severely under utilized. It is estimated that in the United States less then 20% of the medical R&D market is captured by the CROs. These figures are far smaller outside of the United States, particularly in Europe and Japan.
Life Cycle
Typically, a clinical trial is carried out in the following manner: At the initiation of a clinical trial, the company sponsoring the trial or the CRO contracted for the trial (the “sponsor”) will select a number of trial investigators. These trial investigators are usually doctors who specialize in the area of medicine relevant to the new medical technology under study. The trial investigators are chosen based upon several criteria, including:    1) The number of trial participants seen and the ability of the trial investigator to accrue trial participants into the study.    2) The facility and support staff available to the trial investigator.    3) The trial investigator's ability to collect and maintain data in a secure fashion without compromising trial participant confidentiality or care.
A trial protocol will be formulated to achieve the desired goals of the trial, and the protocol will be presented for review and approval before an Institutional Review Board (IRB). The IRB is a committee consisting of peers and people with experience in the research field. It may consist of physicians, nurses, PhD's, bio-statisticians, bio-ethicists, and/or others qualified to evaluate research on human. The IRB evaluates research protocols to assure scientific integrity while maintaining the trial participants' safety and privacy within a standard of ethics acceptable for human experimentation. Once a clinical trial is under way, the trial investigators do the following:    1) Begin recruiting trial participants that fit the inclusion/exclusion criteria of the protocol.    2) Explain the risks and benefits of the trial to the trial participants.    3) Ask the trial participants to give an informed consent.    4) Apply new medical technology, i.e., administer medical treatments.    5) Initiate and continue trial data collection.
The trial data is collected by the trial investigators in the form of reports that are then forwarded to the sponsor. Reporting generally takes the form of paper sheets that are handwritten and transmitted via fax or placed into digital form with the use of an electronic scanner. These reports generally serve as the data collection vehicle with various parameters studied as outlined in the particular protocol. The parameters studied in a clinical trial may include subjective findings such as trial participants' complaints, satisfaction, or symptoms. Objective parameters may also be studied, which parameters include physical examination, laboratory or radiological tests, and other measured findings. Finally, a separate parameter followed in almost all trials is incidence of adverse events or complications from the treatment.
In the course of a clinical trial, an important responsibility is that of a trial monitor. The trial monitor is a person who is usually hired by a CRO to verify that the data reported by the trial investigators corresponds to the source documentation, i.e., the trial participants' clinic records. The trial monitor serves as an auditor of the trial investigators to police the integrity of the data collected. The trial monitor also assures that all documentation, such as each trial participant's informed consent, is properly signed and that the trial investigators stay true to the procedure set forth in the trial protocol. The trial monitor also checks to assure that the reports forwarded to the sponsor correspond to the actual medical records documented by a trial investigator in a trial participant's chart.
As the clinical trial progresses, the sponsor is made cognizant of the overall status of the trial. For example, if an inordinate number of complications arise from the medical treatment, it is the sponsor's responsibility to know of the problem and to react. Sometimes such reactions may prematurely halt the trial. Conversely, it is not uncommon for the new medical technology to be so effective that the reaction and the responsibility of the sponsor is to offer the new medical technology to more trial participants.
At the end of the trial, a stage of trial “closing” is conducted. During this stage all reports are finalized and any missing data is reconciled by the trial investigators. After this, the sponsor consolidates the data collected during the trial for statistical analysis. The results of such analysis are then made available for reporting to the regulatory bodies and/or academic publishing.
Detriments
There are many instances where the life cycle described above falls short of its optimal potential. In fact, negative reports and issues of the shortcomings of medical R&D are in the news daily. In January 2000, all human gene therapy experiments carried out at an Ivy League university and sponsored by the United States government was halted after the death of a trial participant. After further review, there was evidence that the trial participant was not provided proper informed consent. In addition to simple human error, there are ample situations where monetary pressure may lead to potential fraud by the trial investigator and/or the sponsor. Such fraud may include the falsification of the trial data, loose interpretation of the trial protocols to allow into a study trial participants who may not be proper candidates, statistical manipulation to allow results to appear better than actual, under-reporting of adverse events, etc. There have even been situations where an entire group of trial participants reported upon in the trial, did not even exist.
In the early 1990's the National Surgical Adjuvant Breast and Bowel Project ran a clinical trial evaluating benefits of performing mastectomy for trial participants with breast cancer versus lumpectomy with or without radiation. During this trial, one of the site directors, the equivalent of the trial investigator, falsified the dates of certain events of the trial, in order to allow ineligible trial participants to appear eligible for the research. This ultimately resulted in a massive government investigation costing millions of dollars, a delay in the availability of the trial results affecting thousands of patients with breast cancer, skepticism concerning the trial results, loss of the trial investigator credibility, and the derailment of the careers of several prominent academic figures.
The potential for similar situations to recur forces the increased stringency of regulatory processes, thus adding to the already long life cycle period required before marketing and sale of the new medical technology.
Consent
It should be noted that in the life cycle of performing clinical research, the solicitation of the proper informed consent from the patient is a critical part of meeting ethical and legal standards. Informed consent is a major area of fraud and error during the clinical research process. These errors and instances of fraud relate to several major areas which include episodes where:                1) The research investigator (typically the doctor responsible for the trial) does not explain the content of the informed consent document for which the patient's signature is solicited;        2) The occurrence of informed consent is backdated;        3) The patient's or investigator's signature is forged on the informed consent.        
Recently the U.S. government has initiated steps to assure better patient safety for enrollees in clinical research projects. At the forefront of this initiative is the implementation of strict guidelines for the execution of informed consents. These guidelines would include intervals during the clinical trial for which the informed consent would be required, or triggering events during the clinical trial process that might alter the implications of trial enrollment for the patient, i.e., the occurrence of adverse events. Additionally, the government will enforce serious penalties for failures to obtain the proper informed consent, including fines of $250,000 per individual and $1 million per institution.
In another governmental initiative the Food and Drug Administration (FDA) laid out guidelines that clearly define the manner in which electronic records can be signed using at least two distinct tokens, such as a user name and password 21 C.F.R. § 11.200(1) (2000). The prerequisite to the use of an electronic signature, however, is that the organization assigning the electronic signature has verified the identity of the individual 21 C.F.R. § 11.100.(b) (2000).
With the proliferation of electronic data collection in clinical research there is and will continue to be an exponentially increasing need for the use of electronic signatures. This increase makes the collection of physical signatures and verification processes unrealistic, especially in cases where geographically broad populations of users must be quickly granted access to a particular system
Evolution
In view of the pressures placed upon the sponsors in terms of time expenditure while sustaining the scientific rigor, several CROs and industry specialists have begun implementing digital formats for data collection. Digital data collection and collaboration of research over digital networks have the potential for multiple advantages. These advantages include the ability to consolidate the trial data into a single database as the trial data is being collected, thus allowing for the analysis of data in real time. In addition, data can be validated upon entry, ultimately resulting in less time spent at the end of the trial to reconcile “loose ends” in the data collection process. These and other advantages of electronic data collection are clearly superior to conventional methods of handwritten forms, scanning, and faxing. However, many concerns still exist over issues of data security, trial participant privacy, and veracity of the collected data.
Furthermore, while electronic data collection has the potential to improve upon the time expenditure in the clinical trial process, it does not resolve the need to vigorously monitor the trial for fraud. In other words, while the electronic data collection makes the clinical trial process faster, it does not improve the scientific rigor with which the trial investigators collect and report upon the trial data.
In any clinical research setting the key event leading to the generation of data is that between two individuals: the trial participant, e.g., a patient, and the trial investigator, e.g., a doctor. In conventional methods, this interaction is the event that is documented in the trial participant's medical records and is a reflection of the trial participant's physical examination, reports of subjective complaints, interpretations of objective testing, and a synthesized analysis of the trial participant's information as a function of the trial investigator's professional training.
The conventional methods of clinical research rely upon a trial investigator's signature on a paper document. This creates ample of opportunity for fraud and an obvious need for strict monitoring. As the clinical research field looks more to digital data capture and transmission, there is a greater need to authenticate the information. While various methods have been proposed for digital authentication of individuals, what is needed is the authentication that a recorded event occurred in a proscribed manner and was performed by authorized personnel. This event may include the interaction between two or more authorized personnel, such as the doctor and patient. Moreover, such authentication must lead to the acceptance or rejection of the trial data in a clinical study or trial.